Combination of selected analgesics and COX-II inhibitors

ABSTRACT

Combinations of certain analgesics with COX-II inhibitors, related pharmaceutical compositions, including advantageous galenical forms containing these combinations, and the use of such combinations in methods of treatment, in particular for the treatment of pain.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of Ser. No. 13/717,977, filed on Dec.18, 2012, which is a division of application Ser. No. 12/834,641, filedJul. 12, 2010, now U.S. Pat. No. 8,420,691, issued Apr. 16, 2013, whichwas a continuation of application Ser. No. 11/133,190, filed May 20,2005, now U.S. Pat. No. 7,786,160, issued Aug. 31, 2010, which in turnwas a continuation of International patent application no.PCT/EP2003/012882, filed Nov. 18, 2003, designating the United States ofAmerica, and published in German as WO 2004/047823 A1, the entiredisclosure of which is incorporated herein by reference. Priority isclaimed based on Federal Republic of Germany patent application nos. DE102 54 785.8, filed Nov. 22, 2002, and DE 103 26 103.6, filed Jun. 6,2003.

FIELD OF THE INVENTION

The invention relates to the combination of analgesics of group A withCOX-II inhibitors of group B, pharmaceutical compositions, includingadvantageous galenical forms containing this combination, and to the usethereof, in particular for the treatment of pain.

BACKGROUND OF THE INVENTION

The treatment of chronic and non-chronic pain conditions is extremelyimportant in medicine. There is currently a worldwide demand foradditional, not exclusively opioid-based, but highly effective, paintreatment. The urgent need for action for patient-oriented andpurposeful treatment of chronic and non-chronic pain conditions, thisbeing taken to mean the successful and satisfactory treatment of painfor the patient, is documented in the large number of scientific paperswhich have recently appeared in the field of applied analgesics andfundamental research work on nociception.

Even if the analgesics that are conventionally used for treating pain,for example opioids, NA- and 5HT-reuptake inhibitors, NSAIDS and alsoCOX inhibitors, are analgesically effective, side effects neverthelesssometimes occur, in particular in the case of the more active opioids.

SUMMARY OF THE INVENTION

One object of the present invention is therefore to provide substancesor substance combinations that are suitable for the treatment of pain,that preferably simultaneously exhibit fewer side effects in the activedoses than is known from the prior art and, in particular, in thecombinations which exhibit a synergistic effect for the treatment ofpain.

Surprisingly, it has been found that a combination of selectedanalgesics of group A with COX-II inhibitors exhibit an outstandinganalgesic effect. Moreover, these combinations have exceededexpectations and, even in small doses, have proven so effective that itwas possible to reduce the dose of the combined active ingredients. Itis thus expected that there will be significantly fewer side effectsthan occur when larger doses are required.

Accordingly, the invention relates to an active ingredient combinationcomprising at least one analgesic compound A and at least one COX-IIinhibitor, with compound A selected from:

group a) containing:

1-phenyl-3-dimethylamino-propane compounds according to general formulaI

whereinX is selected from OH, F, Cl, H or OC(O)R⁷, where R⁷ is selected frombranched or unbranched, saturated or unsaturated, unsubstituted orsingly or multiply substituted C₁₋₃ alkyl,R¹ is selected from branched or unbranched, saturated or unsaturated,unsubstituted or singly or multiply substituted C₁₋₄ alkyl,R² and R³ respectively independently of one another are selected frombranched or unbranched, saturated or unsaturated, unsubstituted orsingly or multiply substituted H or C₁₋₄ alkyl,orR² and R³ together form a saturated, unsubstituted or singly or multiplysubstituted C₄₋₇ cycloalkyl radical,R⁹ to R¹³ respectively independently of one another are selected from H,F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃,SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; branched orunbranched, saturated or unsaturated, unsubstituted or singly ormultiply substituted C₁₋₆ alkyl; unsubstituted or singly or multiplysubstituted phenyl;where R¹⁴ is selected from C₁₋₆ alkyl; respectively unsubstituted orsingly or multiply substituted pyridyl, thienyl, thiazolyl, phenyl,benzyl or phenethyl; PO(O—C₁₋₄ alkyl)₂, CO(OC₁₋₅ alkyl), CONH—C₆14-(C₁₋₃alkyl), CO(C₁₋₅ alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ isortho-OCOC₁₋₃ alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is C₁₋₄ alkylor 4-morpholino, wherein the alkyl groups in the radicals R¹⁴, R¹⁵ andR¹⁶ may be branched or unbranched, saturated or unsaturated,unsubstituted or singly or multiply substituted;R¹⁷ and R¹⁸ respectively independently of one another are selected fromH; branched or unbranched, saturated or unsaturated, unsubstituted orsingly or multiply substituted C₁₋₆ alkyl; respectively unsubstituted orsingly or multiply substituted phenyl, benzyl or phenethyl,or

R⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O, OCH═CH,CH═CHO, CH═C(CH3)O, OC(CH3)=CH, (CH₂)₄ or OCH═CHO ring,

optionally in the form of their racemates, their pure stereoisomers, inparticular enantiomers or diastereomers, or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany mixing ratio; in the illustrated form or in the form of their acidsor their bases or in the form of their salts, in particular thephysiologically acceptable salts, or in the form of their solvates, inparticular the hydrates;group b) containing:substituted 6-dim ethyl aminomethyl-1-phenyl-cyclohexane compoundsaccording to general formula II

whereinX is selected from OH, F, Cl, H or OC(O)R⁷, where R⁷ is selected frombranched or unbranched, saturated or unsaturated, unsubstituted orsingly or multiply substituted C₁₋₃ alkyl,R¹ is selected from C₁₋₄ alkyl, benzyl, CF₃, OH, OCH₂—C₆H₅, O—C₁₋₄alkyl, Cl or F andR⁹ to R¹³ respectively independently of one another are selected from H,F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃,SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; branched orunbranched, saturated or unsaturated, unsubstituted or singly ormultiply substituted C₁₋₆ alkyl; unsubstituted or singly or multiplysubstituted phenyl;where R¹⁴ is selected from C₁₋₆ alkyl; respectively unsubstituted orsingly or multiply substituted pyridyl, thienyl, thiazolyl, phenyl,benzyl or phenethyl; PO(O—C₁₋₄ alkyl)₂, CO(OC₁₋₅ alkyl), CONH—C₆H₄—(C₁₋₃alkyl), CO(C₁₋₅ alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ isortho-OCOC₁₋₃ alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is C₁₋₄ alkylor 4-morpholino, wherein the alkyl groups in the radicals R¹⁴, R¹⁵ andR¹⁶ may be branched or unbranched, saturated or unsaturated,unsubstituted or singly or multiply substituted;where R¹⁷ and R¹⁸ respectively independently of one another are selectedfrom H; branched or unbranched, saturated or unsaturated, unsubstitutedor singly or multiply substituted C₁₋₆ alkyl; respectively unsubstitutedor singly or multiply substituted phenyl, benzyl or phenethyl,orR⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O, OCH═CH,CH═CHO, CH═C(CH3)O, OC(CH3)=CH, (CH₂)₄ or OCH═CHO ring,optionally in the form of their racemates, their pure stereoisomers, inparticular enantiomers or diastereomers, or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany mixing ratio; in the illustrated form or in the form of their acidsor their bases or in the form of their salts, in particular thephysiologically acceptable salts, or in the form of their solvates, inparticular the hydrates;and/orgroup c) containing:6-dimethyl aminomethyl-1-phenyl-cyclohexane compounds according togeneral formula III

whereinX is selected from OH, F, Cl, H or OC(O)R⁷, where R⁷ is selected frombranched or unbranched, saturated or unsaturated, unsubstituted orsingly or multiply substituted C₁₋₃ alkyl, andR⁹ to R¹³ respectively independently of one another are selected from H,F, Cl, Br, I, CH₂F, CHF₂, CF₃, OH, SH, OR¹⁴, OCF₃, SR¹⁴, NR¹⁷R¹⁸, SOCH₃,SOCF₃; SO₂CH₃, SO₂CF₃, CN, COOR¹⁴, NO₂, CONR¹⁷R¹⁸; branched orunbranched, saturated or unsaturated, unsubstituted or singly ormultiply substituted C₁₋₆ alkyl; unsubstituted or singly or multiplysubstituted phenyl;where R¹⁴ is selected from C₁₋₆ alkyl; respectively unsubstituted orsingly or multiply substituted pyridyl, thienyl, thiazolyl, phenyl,benzyl or phenethyl; PO(O—C₁₋₄ alkyl)₂, CO(OC₁₋₆ alkyl), CONH—C₆H₄—(C₁₋₃alkyl), CO(C₁₋₆ alkyl), CO—CHR¹⁷—NHR¹⁸, CO—C₆H₄—R¹⁵, where R¹⁵ isortho-OCOC₁₋₃ alkyl or meta- or para-CH₂N(R¹⁶)₂ where R¹⁶ is C₁₋₄ alkylor 4-morpholino, wherein the alkyl groups in the radicals R¹⁴, R¹⁵ andR¹⁶ may be branched or unbranched, saturated or unsaturated,unsubstituted or singly or multiply substituted;where R¹⁷ and R¹⁸ respectively independently of one another are selectedfrom H; branched or unbranched, saturated or unsaturated, unsubstitutedor singly or multiply substituted C₁₋₆ alkyl; respectively unsubstitutedor singly or multiply substituted phenyl, benzyl or phenethyl,orR⁹ and R¹⁰ or R¹⁰ and R¹¹ together form an OCH₂O, OCH₂CH₂O, OCH═CH,CH═CHO, CH═C(CH3)O, OC(CH3)=CH, (CH₂)₄ or OCH═CHO ring,with the condition with that if R⁹, R¹¹ and R¹³ correspond to H, and oneof R¹⁰ or R¹² corresponds to H and the other to OCH₃, X may not be OH,optionally in the form of their racemates, their pure stereoisomers, inparticular enantiomers or diastereomers, or in the form of mixtures ofthe stereoisomers, in particular the enantiomers or diastereomers, inany mixing ratio; in the illustrated form or in the form of their acidsor their bases or in the form of their salts, in particular thephysiologically acceptable salts, or in the form of their solvates, inparticular the hydrates.

In the context of this invention, alkyl and cycloalkyl radicals aretaken to mean saturated and unsaturated (but not aromatic), branched,unbranched and cyclic hydrocarbons which may be unsubstituted or singlyor multiply substituted. In this case C₁₋₂ alkyl represents C1 or C2alkyl, C₁₋₃ alkyl represents C1, C2 or C3 alkyl, C₁₋₄ alkyl representsC1, C2, C3 or C4 alkyl, C₁₋₅ alkyl represents C1, C2, C3, C4 or C5alkyl, C₁₋₆ alkyl represents C1, C2, C3, C4, C5 or C6 alkyl, C₁₋₇ alkylrepresents C1, C2, C3, C4, C5, C6 or C7 alkyl, C₁₋₅ alkyl represents C1,C2, C3, C4, C5, C6, C7 or C8 alkyl, C₁₋₁₀ alkyl represents C1, C2, C3,C4, C5, C6, C7, C8, C9 or C10 alkyl and C₁₋₁₅ alkyl represents C1, C2,C3, C4, C5, C6, C7, C8, C9, C10, C11, C12, C13, C14, C15, C16, C17 orC18 alkyl. Furthermore C₃₋₄ cycloalkyl represents C3 or C4 cycloalkyl,C₃₋₅ cycloalkyl represents C3, C4 or C5 cycloalkyl, C₃₋₆ cycloalkylrepresents C3, C4, C5 or C6 cycloalkyl, C₃₋₇ cycloalkyl represents C3,C4, C5, C6 or C7 cycloalkyl, cycloalkyl represents C3, C4, C5, C6, C7 orC8 cycloalkyl, C₄₋₅ cycloalkyl represents C4 or C5 cycloalkyl, C₄₋₆cycloalkyl represents C4, C5 or C6 cycloalkyl, C₄₋₇ cycloalkylrepresents C4, C5, C6 or C7 cycloalkyl, C₅₋₆ cycloalkyl represents C5 orC6 cycloalkyl and C₅₋₇ cycloalkyl represents C5, C6 or C7 cycloalkyl.With respect to cycloalkyl, the term also comprises saturatedcycloalkyls, in which one or two carbon atoms are replaced by aheteroatom, S, N or O. However, the term cycloalkyl also includes singlyor multiply, preferably singly, unsaturated cycloalkyls without aheteroatom in the ring, if the cycloalkyl is not an aromatic system. Thealkyl and cycloalkyl radicals are preferably methyl, ethyl, vinyl(ethenyl), propyl, allyl (2-propenyl), 1-propinyl, methylethyl, butyl,1-methylpropyl, 2-methylpropyl, 1,1-dimethylethyl, pentyl,1,1-dimethylpropyl, 1,2-dimethylpropyl, 2,2-dimethylpropyl, hexyl,1-methylpentyl, cyclopropyl, 2-methylyclopropyl, cyclopropylmethyl,cyclobutyl, cyclopentyl, cyclopentylmethyl, cyclohexyl, cycloheptyl,cyclooctyl, but also adamantyl, CHF₂, CF₃ or CH₂OH and pyrazolinone,oxopyrazolinone, [1,4]dioxan or dioxolan.

In this case, in conjunction with alkyl and cycloalkyl—unless this isnot explicitly defined otherwise—the term substituted in the context ofthis invention denotes the substitution of at least one (optionally alsomore) hydrogen radical(s) for F, Cl, Br, I, NH₂, SH, OCH₃, SCH₃,N(CH₃)₂, NHCH₃ or OH, wherein “multiply substituted” or “substituted”with multiple substitution denotes that the substitution is made both ondifferent and on the same atoms multiply with the same or differentsubstituents, for example threefold on the same carbon atom as in thecase of CF₃ or at different points as in the case of—CH(OH)—CH═CH—CHCl₂. Particularly preferred substituents in this caseare F, Cl and OH. With respect to cycloalkyl, the hydrogen radical canalso be replaced by OC₁₋₃ alkyl or C₁₋₃ alkyl (singly or multiplysubstituted or unsubstituted respectively), in particular methyl, ethyl,n-propyl, i-propyl, CF₃, methoxy or ethoxy.

The term (CH₂)₃₋₆ is taken to mean —CH₂—CH₂—CH₂—, —CH₂—CH₂—CH₂—CH₂—,—CH₂—CH₂—CH₂—CH₂—CH₂— and CH₂—CH₂—CH₂—CH₂—CH₂—CH₂—, (CH₂)₁₋₄ to mean—CH₂—, —CH₂—CH₂—, —CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—, (CH₂)₄₋₅ to mean—CH₂—CH₂—CH₂—CH₂— and —CH₂—CH₂—CH₂—CH₂—CH₂—, etc.

An aryl radical denotes ring systems with at least one aromatic ring butwithout heteroatoms even in only one of the rings. Examples are phenyl,naphthyl, fluoroanthenyl, fluorenyl, tetralinyl or indanyl, which can beunsubstituted or singly or multiply substituted.

A heteroaryl radical denotes heterocyclic ring systems with at least oneunsaturated ring, which contain one or more heteroatoms from the groupcomprising nitrogen, oxygen and/or sulphur and which can also be singlyor multiply substituted. Examples from the group of heteroaryls includefuran, benzofuran, thiophene, benzothiophene, pyrrole, pyridine,pyrimidine, pyrazine, quinoline, isoquinoline, phthalazine,benzo[1,2,5]thiadiazole, benzothiazole, indole, benzotriazole,benzodioxolan, benzodioxan, carbazole, indole and quinazoline.

In this case, in conjunction with aryl and heteroaryl, substituteddenotes the substitution of the aryl or heteroaryl by R²², OR²², ahalogen, preferably F and/or Cl, a CF₃, a CN, a NO₂, a NR²³R²⁴, a C₁₋₆alkyl (saturated), a C₁₋₆ alkoxy, a C₃₋₈ cycloalkoxy, a C₃₋₈ cycloalkylor a C₂₋₆ alkylene.

In this case the radical R²² represents H, a C₁₋₁₀ alkyl, preferably aC₁₋₆ alkyl, an aryl or heteroaryl radical or an aryl or heteroarylradical bound by C₁₋₃ alkyl, saturated or unsaturated, or a C₁₋₃alkylene-group-bound aryl or heteroaryl radical, wherein these aryl orheteroaryl radicals must not themselves be substituted by aryl orheteroaryl radicals.

The radicals R²³ and R²⁴, which may be the same or different, representH, a C₁₋₁₀ alkyl, preferably a C₁₋₆ alkyl, an aryl radical, a heteroarylradical or an aryl or heteroaryl radical bound by saturated orunsaturated C₁₋₃ alkyl or a C₁₋₃ alkylene-group-bound aryl or heteroarylradical, wherein these aryl or heteroaryl radicals must not themselvesbe substituted by aryl or heteroaryl radicals,

or the radicals R²³ and R²⁴ together mean CH₂CH₂OCH₂CH₂,CH₂CH₂NR²⁵CH₂CH₂ or (CH₂)₃₋₆.

The radical R²⁵ represents H, a C₁₋₁₀ alkyl, preferably a C₁₋₆ alkyl, anaryl radical, a heteroaryl radical or an aryl or heteroaryl radicalbound by saturated or unsaturated C₁₋₃ alkyl or a C₁₋₃alkylene-group-bound aryl or heteroaryl radical, wherein these aryl orheteroaryl radicals must not themselves be substituted by aryl orheteroaryl radicals.

The term “salt” denotes any form of the active ingredient according tothe invention in which it assumes or is charged with an ionic form andis coupled to a counter ion (a cation or anion) or is in solution. Thisalso includes complexes of the active ingredient with other moleculesand ions, in particular complexes which are complexed by ioninteraction. In particular this is taken to mean (and this is also apreferred embodiment of this invention) physiologically acceptablesalts, in particular physiologically acceptable salts with cations orbases and physiologically acceptable salts with anions or acids or evena salt formed with a physiologically acceptable acid or physiologicallyacceptable cation.

The “term physiologically acceptable salt with anions or acids” denotes,in the context of this invention, salts of at least one of the compoundsaccording to the invention—usually protonated, for example onnitrogen—as a cation with at least one anion which are physiologicallyacceptable—in particular when administered to humans and/or mammals. Inthe context of this invention this denotes, in particular, the saltformed with a physiologically acceptable acid, namely salts of therespective active ingredient with inorganic or organic acids, which arephysiologically acceptable—in particular when administered to humansand/or mammals. Examples of physiologically acceptable salts of specificacids are salts of: hydrochloric acid, hydrobromic acid, sulphuric acid,methane sulphonic acid, formic acid, acetic acid, oxalic acid, succinicacid, malic acid, tartaric acid, mandelic acid, fumaric acid, lacticacid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1b6-benzo[d]isothiazol-3-one (saccharic acid),monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid,nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoicacid, α-lipoic acid, acetyl glycine, acetylsalicylic acid, hippuric acidand/or aspartic acid. Hydrochloride salt and citrate are particularlypreferred.

The term “salt formed with a physiologically acceptable acid”, in thecontext of this invention, is taken to mean salts of the respectiveactive ingredient with inorganic or organic acids which arephysiologically acceptable—in particular when administered to humansand/or mammals. Hydrochloride and citrate are particularly preferred.Examples of physiologically acceptable acids include: hydrochloric acid,hydrobromic acid, sulphuric acid, methane sulphonic acid, formic acid,acetic acid, oxalic acid, succinic acid, tartaric acid, mandelic acid,fumaric acid, lactic acid, citric acid, glutamic acid,1,1-dioxo-1,2-dihydro1λ6-benzo[d]isothiazol-3-one (saccharic acid),monomethyl sebacic acid, 5-oxo-proline, hexane-1-sulphonic acid,nicotinic acid, 2-, 3- or 4-amino benzoic acid, 2,4,6-trimethyl-benzoicacid, α-lipoic acid, acetyl glycine, acetylsalicylic acid, hippuric acidand/or aspartic acid.

The term “physiologically acceptable salt with cations or bases”denotes, in the context of this invention, salts of at least one of thecompounds according to the invention—usually a (deprotonated) acid—as ananion with at least one, preferably inorganic, cation, which arephysiologically acceptable, in particular when administered to humansand/or mammals. The salts of the alkali and alkaline-earth metals areparticularly preferred, but also NH₄ ⁺, in particular however (mono) or(di) sodium, (mono) or (di) potassium, magnesium or calcium salts.

The term “salt formed with a physiologically acceptable cation” is takento mean, in the context of this invention, salts of at least one of therespective compounds as an anion with at least one inorganic cation,which are physiologically acceptable, in particular when administered tohumans and/or mammals. The salts of the alkali and alkaline-earth metalsare particularly preferred, but also NH₄ ⁺, in particular however (mono)or (di) sodium, (mono) or (di) potassium, magnesium or calcium salts.

Compounds of group a) and the production thereof are known from U.S.Pat. No. 6,248,737 (=DE 44 26 245). Compounds of groups b) and c) andthe production thereof are known from U.S. Pat. No. 5,733,936 (=DE 19525 137).

The term “COX-II inhibitors” refers to selective inhibitors of COX II,the inducible isoform of cyclooxygenase. Cyclooxygenase is a synonym forprostaglandin endoperoxide synthase; an enzyme that combines thefunction of a dioxgenase and a peroxidase and, as a key enzyme,catalyses the conversion of arachidonic acid into prostaglandin H2 orperoxides (see Walter de Gruyter, Pschyrembel, 258^(th) edition; RocheLexikon Medizin, 4^(th) edition). Further information regarding COX-IIinhibitors, in particular listings thereof, may be found on pp. 13 to126 and in particular 21 to 31 of “Analgesics, From Chemistry andPharmacology to Clinical Application”; Buschmann et al (eds.), 1^(st)edition, Wiley-VCH, 2002. All of the content of this chapter is part ofthe description of this invention. The term “COX-II inhibitors” refersin particular, by way of example, to Celecoxib, Rofecoxib, Etoricoxib,Valdecoxib, Parecoxib, Etodolac, Meloxicam or Nimesulide. Celecoxib,which is sold under the name LOSEC® or Prilosec® or CELEBREX®, andRofecoxib, which is sold under the name VIOXX®, are of particularimportance. The term “selectively correspondingly preferred” denotesthat the compound displays more pronounced inhibition of COX II than ofCOX I and/or in particular exhibits an IC₅₀ that is ≥5 lower on COX IIthan on COX 1.

In a preferred embodiment, for the combination according to theinvention, compound A in group a) is selected from compounds accordingto formula I, in which:

X is selected from

OH, F, Cl, OC(O)CH₃ or H, preferably OH, F, OC(O)CH₃ or H,

and/or

R¹ is selected from

saturated and unsubstituted, branched or unbranched C₁₋₄ alkyl;preferably CH₃, C₂H₅, C₄H₉ or t-butyl, in particular CH₃ or C₂H₅,

and/or

R² and R³ independently of one another are selected from

saturated and unsubstituted, branched or unbranched H, C₁₋₄ alkyl;preferably H, CH₃, C₂H₅, i-propyl or t-butyl, in particular H or CH₃,preferably R³=H,

or

R² and R³ together form a saturated or unsaturated, unsubstituted orsingly or multiply substituted, preferably saturated and unsubstitutedC₅₋₆ cycloalkyl radical, in particular cyclohexyl.

and/or

R⁹ to R¹³, wherein three or four of the radicals R⁹ to R¹³ mustcorrespond to H, independently of one another are selected from

H, Cl, F, OH, CF₂H, CF₃ or saturated and unsubstituted, branched orunbranched C₁₋₄ alkyl; OR¹⁴ or SR¹⁴, where R¹⁴ is selected fromsaturated and unsubstituted, branched or unbranched C₁₋₃ alkyl;

preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃

or R¹² and R¹¹ form a 3,4-OCH═CH ring

in particular

if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also correspondsto H, whereas the other is selected from:

Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H, OCH₃ or SCH₃

or

if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH, OCH₃, Cl or F,preferably Cl, one of R¹⁰ or R¹² also corresponds to H, whereas theother corresponds to OH, OCH₃, Cl or F, preferably Cl,

or

if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is selected from CF₃, CF₂H,Cl or F, preferably F,

or

If R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R₁₃ also correspondsto H, whereas the other is selected from OH, OC₂H₅ or OC₃H₇.

In particular for compounds of group a), compounds of formula I, whereinR³=H, are in the form of the diastereomers having the relativeconfiguration Ia

in particular in mixtures having a relatively high content of thisdiastereomer in comparison to the other diastereomer, or are used as apure diastereomer.

In particular for compounds of group a), compound A, which is selectedfrom the following group, is used:

-   (2RS,3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,-   (+)-(2R,3R)-1-dimethylamino-3-(3-methoxy-phenyl)-2-methyl-pentan-3-ol,-   (2RS,3RS)-3-(3,4-dichlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,-   (2RS,3RS)-3-(3-difluoromethyl-phenyl)-1-dimethylamino-2-methyl-pentan-3-ol,-   (2RS,3RS)-1-dimethylamino-2-methyl-3-(3-methylsulphanylphenyl)-pentan-3-ol,-   (3RS)-1-dimethylamino-3-(3-methoxy-phenyl)-4,4-dimethyl-pentan-3-ol,-   (2RS,3RS)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,-   (1RS,2RS)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,-   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,-   (+)-(1R,2R)-3-(3-dimethylamino-1-hydroxy-1,2-dimethyl-propyl)-phenol,-   (−)-(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol,-   (+)-(1R,2R)-acetic    acid-3-dimethylamino-1-ethyl-1-(3-methoxy-phenyl)-2-methyl-propylester,-   (1RS)-1-(1-dimethylaminomethyl-cyclohexyl)-1-(3-methoxy-phenyl)-propan-1-ol,-   (2RS,3RS)-3-(4-chlorophenyl)-1-dimethylamino-2-methyl-pentan-3-ol,-   (+)-(2R,3R)-3-(3-dimethylamino-1-ethyl-1-hydroxy-2-methyl-propyl)-phenol,-   (2RS,3RS)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol-   (+)-(2R,3R)-4-dimethylamino-2-(3-methoxy-phenyl)-3-methyl-butan-2-ol,    preferably as the hydrochloride.

In a preferred embodiment, for the combination according to theinvention, compound A in group b) is selected from compounds accordingto formula II, in which:

X is selected from

OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in particular OH,

and/or

R¹ is selected from

C₁₋₄ alkyl, CF₃, OH, O—C₁₋₄ alkyl, Cl or F, preferably OH, CF₃ or CH₃,

and/or

R⁹ to R¹³, wherein three or four of the radicals R⁹ to R¹³ mustcorrespond to H, independently of one another are selected from

H, Cl, F, OH, CF₂H, CF₃ or saturated and unsubstituted, branched orunbranched C₁₋₄ alkyl; OR¹⁴ or SR¹⁴, where R¹⁴ is selected fromsaturated and unsubstituted, branched or unbranched C₁₋₃ alkyl;

preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃

or R¹² and R¹¹ form a 3,4-OCH═CH ring,

in particular

if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also correspondsto H, whereas the other is selected from:

Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H, OR¹⁴ or SCH₃,in particular OH or OC₁₋₃ alkyl, preferably OH or OCH₃, or,

if R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH, OCH₃, Cl or F,preferably Cl, one of R¹⁰ or R¹² also corresponds to H, whereas theother corresponds to OH, OCH₃, Cl or F, preferably Cl,

or

if R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is selected from CF₃, CF₂H,Cl or F, preferably F,

or

if R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also correspondsto H, whereas the other is selected from OH, OC₂H₅ or OC₃H₇,

particularly preferably,

if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also correspondsto H, whereas the other is selected from:

Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or OR¹⁴, inparticular OH or OC₁₋₃ alkyl, preferably OH or OCH₃.

In particular for compounds of group b), compounds of formula II are inthe form of the diastereomers having the relative configuration IIa

in particular in mixtures having a relatively high content of thisdiastereomer in comparison to the other diastereomer, or are used as apure diastereomer.

In particular for compounds of group b), compound A, which is selectedfrom the following group, is used:

-   (1    RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,-   (+)-(1R,3R,6R)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,-   (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3-hydroxy-phenyl)-cyclohexane-1,3-diol,-   (1RS,3SR,6RS)-6-dimethylaminomethyl-1-(3-methoxy-phenyl)-cyclohexane-1,3-diol,-   (+)-(1R,2R,5S)-3-(2-dimethylaminomethyl-1-hydroxy-5-methyl-cyclohexyl)-phenol    or-   (1RS,2RS,5RS)-3-(2-dimethylaminomethyl-1-hydroxy-5-trifluoromethyl-cyclohexyl)-phenol,    preferably as the hydrochloride.

In a preferred embodiment, for the combination according to theinvention, compound A in group c) is selected from compounds accordingto formula III, in which:

X is selected from

OH, F, Cl, OC(O)CH₃ or H, preferably OH, F or H, in particular F or H.

and/or

R⁹ to R¹³, wherein three or four of the radicals R⁹ to R¹³ mustcorrespond to H, independently of one another are selected from H, Cl,F, OH, CF₂H, CF₃ or saturated and unsubstituted, branched or unbranchedC₁₋₄ alkyl; OR¹⁴ or SR¹⁴, where R¹⁴ is selected from saturated andunsubstituted, branched or unbranched C₁₋₃ alkyl;preferably H, Cl, F, OH, CF₂H, CF₃, OCH₃ or SCH₃or R¹² and R¹¹ form a 3,4-OCH═CH ring,characterized in that, in particular,if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also correspondsto H, whereas the other is selected from:Cl, F, OH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH, CF₂H, OR¹⁴ or SCH₃,in particular OH or OC₁₋₃ alkyl, preferably OH or OCH₃,orif R⁹ and R¹³ correspond to H and R¹¹ corresponds to OH, OCH₃, Cl or F,preferably Cl, one of R¹⁰ or R¹² also corresponds to H, whereas theother corresponds to OH, OCH₃, Cl or F, preferably Cl,orif R⁹, R¹⁰, R¹² and R¹³ correspond to H, R¹¹ is selected from CF₃, CF₂H,Cl or F, preferably F,orif R¹⁰, R¹¹ and R¹² correspond to H, one of R⁹ or R¹³ also correspondsto H, whereas the other is selected from OH, OC₂H₅ or OC₃H₇,particularly preferably,if R⁹, R¹¹ and R¹³ correspond to H, one of R¹⁰ or R¹² also correspondsto H, whereas the other is selected from:Cl, F, OH, SH, CF₂H, CF₃, OR¹⁴ or SR¹⁴, preferably OH or OR¹⁴, inparticular OH or OC₁₋₃ alkyl, preferably OH or OCH₃.

In particular for compounds of group c), compounds of formula III are inthe form of their diastereomers having the relative configuration IIIa

in particular in mixtures having a relatively high content of thisdiastereomer in comparison to the other diastereomer, or are used as apure diastereomer.

In particular for compounds of group c), compound A, which is selectedfrom the following group, is used:

-   (+)-(1R,2R)-3-(2-dimethylaminomethyl-1-fluoro-cyclohexyl)-phenol,-   (+)-(1S,2S)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol or-   (−)-(1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol,    preferably as the hydrochloride.

In a preferred embodiment, for the combination according to theinvention, the COX-II inhibitor (compound B) is selected from:

Celecoxib, Rofecoxib, Etoricoxib, Valdecoxib, Parecoxib, Etodolac,Meloxicam or Nimesulide, in particular

Celecoxib or Rofecoxib.

The active ingredient combinations according to the invention aretoxicologically safe, so the invention also relates to a pharmaceuticalcomposition containing an active ingredient combination according to theinvention; and optionally suitable additives and/or auxiliaries oractive ingredients;

Suitable additives and/or auxiliaries, in the context of this invention,are any substances known to a person skilled in the art from the priorart for obtaining galenical formulations. The choice of theseauxiliaries and the amounts thereof to be used depend on whether thepharmaceutical preparation is to be administered orally, intravenously,intraperitoneally, intradermally, intramuscularly, intranasally,buccally, rectally or topically. Preparations in the form of tablets,chewing tablets, dragees, capsules, granules, drops, juices or syrupsare suitable for oral administration, solutions, suspensions, easilyreconstitutable dry preparations and sprays are suitable for parenteral,topical and inhalative administration. Suppositories for rectaladministration are a further possibility. Administration in a deposit,in dissolved form, in a carrier foil or a plaster, optionally with theaddition of agents to promote skin penetration, are examples of suitablepercutaneous administration preparations. Examples of auxiliaries andadditives for oral administration preparations include blasting agents,lubricants, binders, fillers, mould release agents, optionally solvents,flavouring agents, sugar, in particular carrier agents, diluents, dyes,antioxidants, etc. Waxes and fatty acid esters may, inter alia, be usedas suppositories and carrier substances, preservatives and suspensionauxiliaries, etc. may be used as parenteral administration agents. Theamount of active ingredient to be administered to the patient varies asa function of the weight of the patient, the method of administrationand the severity of the illness. The compounds according to theinvention may be released after a delay from preparations that may beadministered orally, rectally or percutaneously. In the indicationaccording to the invention, suitable retarding formulations, in the formof a “once-daily” preparation that only has to be taken once a day, areparticularly preferred.

Also preferred are pharmaceutical compositions containing at least 0.05to 90.0% of the active ingredient combination, in particular loweffective doses, in order to prevent side effects or analgesic effects.Conventionally, 0.1 to 5000 mg of the combination per kg of body weight,in particular 1 to 500 mg per kg, preferably 2 to 250 mg per kg areadministered. Also preferred and conventional, however, is theadministration of 0.01 to 5 mg/kg, preferably 0.03 to 2 mg/kg, inparticular 0.05 to 1 mg/kg of body weight.

Examples of auxiliaries may include: water, ethanol, 2-propanol,glycerol, ethylene glycol, propylene glycol, polyethylene glycol,polypropylene glycol, glucose, fructose, lactose, saccharose, dextrose,molasses, starch, modified starch, gelatine, sorbitol, inositol,mannitol, microcrystalline cellulose, methyl cellulose, carboxymethylcellulose, cellulose acetate, shellac, cetyl alcohol, polyvinylpyrrolidone, paraffins, waxes, natural and synthetic gums, acacia gum,alginates, dextran, saturated and unsaturated fatty acids, stearic acid,magnesium stearate, zinc stearate, glycerol stearate, sodium laurylsulphate, edible oils, sesame oil, coconut oil, peanut oil, soybean oil,lecithin, sodium lactate, polyoxyethylene and polypropylene fatty acidester, sorbitan fatty acid ester, sorbic acid, benzoic acid, citricacid, ascorbic acid, tannic acid, sodium chloride, potassium chloride,magnesium chloride, calcium chloride, magnesium oxide, zinc oxide,silicon dioxide, titanium oxide, titanium dioxide, magnesium sulphate,zinc sulphate, calcium sulphate, potash, calcium phosphate, dicalciumphosphate, potassium bromide, potassium iodide, talcum, kaolin, pectin,Crospovidon, agar and bentonite.

The pharmaceutical compositions according to the invention are producedusing means, devices, methods and processes that are well known in theprior art of pharmaceutical formulations, as described for example in“Remington's Pharmaceutical Sciences”, A. R. Gennaro (ed.), 17^(th)edition, Mack Publishing Company, Easton, Pa. (1985), in particular inpart 8, chapters 76 to 93.

Thus, for a solid formulation, such as a tablet, for example, the activeingredient of the pharmaceutical composition may be granulated with apharmaceutical carrier, for example conventional tablet ingredients suchas corn starch, lactose, saccharose, sorbitol, talcum, magnesiumstearate, dicalcium phosphate or pharmaceutically acceptable gums, andpharmaceutical diluents, for example water, in order to form a solidcomposition that contains an active ingredient in homogeneousdistribution. The term “homogeneous distribution” is taken to mean thatthe active ingredient is distributed uniformly over the entirecomposition, so that said composition may easily be divided into equallyeffective unit dose forms, such as tablets, pills or capsules. The solidcomposition is then divided into unit dose forms. The tablets or pillsof the pharmaceutical composition according to the invention or of thecompositions according to the invention may also be coated or compoundedin a different manner, in order to provide a dose form with a delayedrelease. Suitable coating agents include polymer acids and mixtures ofpolymer acids with materials such as shellac, cetyl alcohol and/orcellulose acetate.

As it has proven particularly preferable if the COX-II inhibitor isgiven before giving the selected analgesic (compound A), in particularat least 30 minutes, preferably 1 hour beforehand, galenicalformulations having a suitable release profile are particularlypreferred. An example of this might be an osmotically driven releasesystem for achieving a delayed release of compound A with a coating thatcontains the COX-II inhibitor and is released correspondingly earlier.In a release system of this kind, which is preferably oral, at leastone, and preferably all, of the surfaces of the release system,preferably that or those that is/are or might be in contact with therelease medium, is/are semipermeable, preferably equipped with asemipermeable coating, so the surface(s) is/are permeable to the releasemedium, but substantially, preferably entirely, impermeable to theactive ingredient, compound A, the surface(s) and/or optionally thecoating comprising at least one opening for releasing the activeingredient, compound A. Moreover, precisely that/those surface(s) thatis/are in contact with the release medium is/are provided with a coatingcontaining and releasing the COX-II inhibitor. This is preferably takento mean a system in tablet form comprising a discharge opening, anosmotic pharmaceutical composition core, a semipermeable membrane and apolymer portion that exerts pressure. A good and preferred example ofthis kind of system is the OROS® System of the ALZA Corporation, USA, ofwhich the website or other forms of product information contain detailsregarding the OROS® System. These are, in particular, the OROS®Push-Pull™ System, the OROS® Delayed Push-Pull™ System, the OROS®Multi-Layer Push-Pull™ system, the OROS® Push-Stick System and also, inspecific cases, the L-OROS™. Embodiments and examples of the specificproduction of osmotically driven release systems may be inferred fromU.S. Pat. Nos. 4,765,989, 4,783,337 and 4,612,008, all of the contentsof which are part of the description of this invention.

A further example is a gel-matrix tablet, such as the products developedby Penwest Pharmaceuticals (for example, under TimeRX). Suitableexamples are provided in U.S. Pat. Nos. 5,330,761, 5,399,362, 5,472,711and 5,455,046. Particularly suitable is a retarding matrix formulation,with an inhomogeneous distribution of the active ingredient combination,the COX-II-inhibitor being found in propagated form in the outer region(the portion that comes into contact with the release medium mostquickly) of the matrix and the selected analgesic (compound A) beingfound in propagated form inside the matrix. On contact with the releasemedium, the outer matrix layer initially (and relatively quickly) swellsand firstly releases the COX-II inhibitor, followed by the significantly(more) retarded release of compound A. Examples of a suitable matrixinclude matrices with 1 to 80% by weight of one or more hydrophilic orhydrophobic polymers as pharmaceutically acceptable matrix formers. Afurther example of a suitable matrix may be found in U.S. Pat. No.4,389,393 (=DE 33 09 516).

The invention also relates to the use of an active ingredientcombination according to the invention for the treatment of pain, inparticular neuropathic, acute, chronic, visceral or cancer pain.

The invention also relates to a method for the treatment of pain inwhich the active ingredient combination according to the invention isused.

A further preferred subject of the invention is a therapy, in particulara therapy regimen, in which, in order to treat pain, the COX-IIinhibitor is given before giving the selected analgesic (compound A), asthis has proven to be particularly advantageous. Particularlypreferably, the COX-II inhibitor is given at least 30 minutes,preferably 1 hour before giving compound A. This may be done, forexample, directly by the relevant doctor, but also (for example, on thedoctor's instructions) by the patient himself. The active ingredientcombination may also be separated into various pharmaceuticalpreparations, and may in particular also be in the form of variouspharmaceutical packages. A possible and also advantageous embodiment ofthis invention would be a kit in which the active ingredients of theactive ingredient combination according to the invention, althoughspatially separated, are provided in a presentation form, for example apharmaceutical composition package. A “kit” of this type is accordinglyalso a preferred embodiment of the invention.

EXAMPLES

The following examples are intended to illustrate and clarify certainembodiments of the invention, however they are not intended to andshould not be understood to limit the subject matter of the invention.

Example 1: Supra-Additive Effect in the Randall-Selitto Test

The compounds, which were tested with regard to their efficacy, arelisted below. The numbering is used in the examples and the figures:

Compound A:

Name Compound No. (1 R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol;1 hydrochloride (1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- 2phenol; Hydrochloride(1S,2S)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)- 3 phenol;Hydrochloride (1RS,3RS,6RS)-6-dimethylaminomethyl-1-(3- 4[methoxy-phenyl)-cyclohexane-1,3-diol; hydrochlorideCOX II-Inhibitors:

Name Compound No. Celecoxib 101 Rofecoxib 102 Celecoxib in the form ofthe final pharmaceutical 103 composition CELEBREX ® Rofecoxib in theform of the final pharmaceutical 104 composition VIOXX ®

BRIEF DESCRIPTION OF THE FIGURES

FIGS. 1 and 2 show the supra-additive effect of the combination of theselected analgesic compound no. 2 (compound A) with the COX-IIinhibitors in the Randall-Selitto test described below, in the case ofstaggered administration. The COX inhibitors (compound 104 or 103) wereadministered perorally to rats 1 hour before the administration ofcompound no. 2. AUD=area under data. % MPE=% of the maximum possibleeffect, wherein the maximum possible effect=100%.

FIG. 3 shows the supra-additive effect of the combination of theselected analgesic compound no. 4 (compound A) with the COX-II inhibitorcompound no. 103 in the Randall-Selitto test, in the case of staggeredadministration, over a period of 75 to 90 min after the administrationof compound 4. The COX inhibitor was administered perorally to rats 1hour before the administration of compound 4.

FIG. 4 shows the supra-additive effect of the combination of theselected analgesic compound no. 1 (compound A) with the COX-II inhibitorcompound no. 103 in the Randall-Selitto test, in the case of staggeredadministration. The duration of the antinociceptive effect with thecombination of compound no. 103 and compound no. 1 was alsosignificantly extended. The COX inhibitor was administered perorally torats 1 hour before the administration of compound no. 1.

FIG. 5 shows the supra-additive effect of the combination of theselected analgesic compound no. 3 (compound A) with the COX-II inhibitorcompound no. 103 in the Randall-Selitto test, in the case of staggeredadministration. The duration of the antinociceptive effect in thecombination of compound no. 103 and compound no. 3 was alsosignificantly extended. The COX inhibitor was administered perorally torats 1 hour before the administration of compound no. 3.

Example 2: Writhing Test on Mouse

The writhing test is a modification of the method of Schmauss C andYaksh TL, J Pharmacol Exp Ther 228: 1-12 (1984) and a model for acutepain.

9% acetic acid was administered to the animals intraperitoneally as apain stimulus. This was administered 30 min (test substance perorally)or 10 min (test substance intravenously) after the administration of thetest substance.

The pain-induced writhing reactions were recorded 10 to 35 min after theadministration of acetic acid. As rats rarely exhibit the conventionalwrithing reaction of mice, but do exhibit other very clear expressionsof pain, the evaluation took place on the basis of a score division.Pain expressions, such as a slanting body angle when the animal standsupright, frequent cleaning of the belly or arching of the back withoutstretching of the rear limbs, were thus included in the evaluation.

The animals that had been treated with the substance were compared witha control group, which had been given physiological saline solution. Thegroup contained 10 animals (n=10).

The result of the active ingredient combination of compound no. 2 withthe COX-II inhibitors 101, 102, 103 and 104 may be inferred from Table1.

Example 3: Formalin Test

The formalin test (Dubuisson, D. and Dennis, S. G., 1977, Pain, 4, 161to 174) is a model for acute and chronic pain. In the tests presentedhere, the chronic pain component was evaluated.

By means of a single formalin injection into the dorsal side of a hindpaw of test animals that were able to move freely, a biphasicnociceptive reaction, which was detected by the observation of threeclearly distinguishable behavioural patterns, was induced.

Formalin having a volume of 20 μl and a concentration of 1% wasadministered subcutaneously into the dorsal side of the right hind pawof each animal. The specific behavioural changes, such as raising andshaking of the paw, weight loss in the animal and biting and lickingreactions, were continuously observed and registered for up to 60 minafter the formalin administration. The behavioural changes were weighteddifferently (a score of 0 to 3) and a pain rate (PR) calculated havingthe general formula:PR=[(T ₀×0)+(T ₁×1)+(T ₂×2)+(T ₃×3)/180.

T₀, T₁, T₂ and T₃ each correspond to the time in seconds during whichthe animal exhibited behavioural pattern 0, 1, 2 or 3. The groupcontained 10 animals (n=10).

The result of the active ingredient combination of compound no. 2 withthe COX-II inhibitors 101, 102, 103 and 104 may be inferred from Table1.

Example 4: Randell-Selitto Test

The Randell-Selitto test of Randall and Selitto (Arch. Int.Pharmacodyn., 1957, 111: 409 to 419) is a model for inflammatory pain.

By means of the injection of 0.1 ml 20% baking yeast suspensionventrally into a hind paw an oedema was induced, on which pain wasgenerated 4 hours later by continuously increasing pressure with a stamp(2 mm tip diameter). The measured value to be determined and at the sametime also the end point of the pain test was the pressure at which thevocalisation reaction of the animal occurred. The percentage maximumpossible effect (% MPE) was calculated. The maximum pressure of thestamp was 250 g. The group size was n=10.

The results of the tests may be inferred from FIGS. 1 to 4 and thefollowing Tables 1 to 4.

Evaluation:

The theoretical additive value was calculated by adding the mean valuesfrom the individual tests of the test substance and COX-II inhibitor.The corresponding standard deviation of the theoretical additive meanvalue was calculated from the addition of the variances.

In all of the above-listed animal models, the selected analgesics(compound A) exhibited a moderately strong to strong inhibition ofnociception or hyperalgesia.

The simultaneous administration of a selective COX-II inhibitor(Rofecoxib or Celecoxib) with compound 1 resulted, in the listed tests,i.e. in acute, in chronic and in inflammatory pain (Table 1), in anintensification of effect in comparison to the theoretically calculatedpurely additive effect. A clear effect-increasing supra-additive effectis to be highlighted in the case of the staggered administration ofCOX-II inhibitor and the selected analgesics (compound A), compound nos.1, 4, 2 and 2 (Randall-Selitto test). In these tests, either Rofecoxibor Celecoxib was administered 1 hour prior to the administration of theselected analgesic (compound A). In a few tests, Rofecoxib wasadministered as the final preparation Vioxx and Celecoxib as Celebrex.

The results of selected tests, in this case, for example, with compoundno. 1, are summarised in the following table (Table 1): Fixed ratiocombination: equieffective dose of the two substances, calculated fromthe ratio of the respective ED50 values. Fixed dose combination: fixeddoses of the respective substances.

TABLE 1 % effect/ Dose of ED50 Ratio of compound A % effect/ [mg/kg] %effect/ Compound compound (1) and % effect/ ED50 of ED50 [mg/kg] No./ A(1) to COX-II ED50 [mg/kg] combination of Test combination COX-IIinhibitor (2) [mg/kg] of (theoretical combination (animal (compoundMethod of inhibitor (2) [mg/kg] of COX-II additive (experimental model)A + COX II) administration 1: 2: 1: 2: compound A inhibitor value)value) Fixed ratio combination Writhing 2 + 102 peroral 1 2 — — ED₅₀:33.0 ED₅₀: 60.1 ED₅₀: 47.0 ED₅₀: 23.3 (rat) Formalin 2 + 101 peroral47.3 52.7 — — ED₅₀: 34.6 ED₅₀: 38.5 ED₅₀: 36.5 ED₅₀: 22.8 test (mouse)Formalin 2 + 101 peroral 10.5 89.5 — — ED₅₀: 18.0 ED₅₀: 154 ED₅₀: 86.0ED₅₀: 60.6 test (rat) Fixed dose combination: Randall- 2 + 104 peroral —— 31 215 13.3 11.2 24.5 29.7 Selitto (rat) Randall- 2 + 101 peroral — —31 215 13.3 9.8 23.1 29.6 Selitto (rat) Fixed dose combination(staggered administration; COX inhibitor 1 hour prior to compound A):Randall- 2 + 104 peroral — — 31 215 20.0 13.0 33.0 45.7 Selitto (rat)Randall- 2 + 104 peroral — — 46 215 32.6 13.0 45.6 59.8 Selitto (rat)Randall- 2 + 103 peroral — — 31 215 20.0 17.3 37.3 60.9 Selitto (rat)Randall- 2 + 103 peroral — — 46 215 32.6 17.3 49.9 86.1 Selitto (rat)

Table 2 shows the tests with compound No. 4 according to Example 4

TABLE 2 Dose of % effect/ % effect/ Ratio of compound % effect/ ED₅₀[mg/kg] ED₅₀ Compound compound A (1) and % effect/ ED₅₀ of [mg/kg] No./A (1) to COX-II ED₅₀ [mg/kg] combination of Test combination COX-IIinhibitor [mg/kg] of (theoretical combination (animal (compound Methodof inhibitor (2) (2) of COX-II additive (experimental model) A + COX II)administration 1: 2: 1: 2: compound A inhibitor value) value) Fixed dosecombination (staggered administration; COX inhibitor 1 hour prior tocompound A) Randall- 4 + 103 peroral — — 68.1 215 85.4 16.7 102.1 109.3Selitto 15-75 min* 15-75 min 15-75 min 15-75 min (rat) Randall- 4 + 103peroral — — 68.1 215 45.2  8.0  53.2  68.5 Selitto 75-90 min* 75-90 min75-90 min 75-90 min (rat) *= evaluated period after administration ofcompound No. 4 (see FIG. 2)

Table 3 shows the tests with compound No. 1 according to Example 4

TABLE 3 Dose of % effect/ % effect/ Ratio of compound % effect/ ED₅₀[mg/kg] ED₅₀ Compound compound A (1) and % effect/ ED₅₀ of [mg/kg] No./A (1) to COX-II ED₅₀ [mg/kg] combination of Test combination COX-IIinhibitor [mg/kg] of (theoretical combination (animal (compound Methodof inhibitor (2) (2) of COX-II additive (experimental model) A + COX II)administration 1: 2: 1: 2: compound A inhibitor value) value) Fixed dosecombination (staggered administration; COX inhibitor 1 hour prior tocompound A) Randall- 1 + 103 peroral — — 46.4 215 26.2 8.9 35.1 84.1Selitto (rat)

Table 4 shows the tests with compound No. 3 according to Example 4

TABLE 4 Dose of % effect/ % effect/ Ratio of compound % effect/ ED₅₀[mg/kg] ED₅₀ Compound compound A (1) % effect/ ED₅₀ of [mg/kg] No./ A(1) to and ED₅₀ [mg/kg] combination of Test combination COX-II COX-II[mg/kg] of (theoretical combination (animal (compound Method ofinhibitor (2) inhibitor of COX-II additive (experimental model) A + COXII) administration 1: 2: 1: 2: compound A inhibitor value) value) Fixeddose combination (staggered administration; COX inhibitor 1 hour priorto compound A) Randall- 1 + 103 peroral — — 21.5 215 22.8 8.9 31.7 96.4Selitto (rat)

Example 6: Parenteral Form of Administration

10 g (1R,2R)-3-(2-dimethylaminomethyl-cyclohexyl)-phenol; hydrochlorideand 20 g Celecoxib were dissolved in 1 l water at room temperature forinjection purposes and then adjusted to isotonic conditions by addingNaCl.

The foregoing description and examples have been set forth merely toillustrate the invention and are not intended to be limiting. Sincemodifications of the described embodiments incorporating the spirit andsubstance of the invention may occur to persons skilled in the art, theinvention should be construed broadly to include all variations fallingwithin the scope of the appended claims and equivalents thereof.

The invention claimed is:
 1. An active ingredient combinationcomprising: at least one analgesic compound selected from the groupconsisting of:(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol; and salts ofthe foregoing with a physiologically tolerated acid; and at least oneCOX-II inhibitor.
 2. The active ingredient combination of claim 1,wherein the analgesic compound is present in the form of a hydrochlorideor citrate salt.
 3. The active ingredient combination of claim 1,wherein the analgesic compound is present in the form of a free base. 4.The active ingredient combination of claim 1, wherein the analgesiccompound is present in the form of an isolated enantiomer or isolateddiastereoisomer.
 5. The active ingredient combination of claim 1,wherein the analgesic compound is present in the form of a mixture ofstereoisomers.
 6. The active ingredient combination of claim 1, whereinthe analgesic compound is present in the form of a racemic mixture. 7.The active ingredient combination of claim 1, wherein the analgesiccompound is present in the form of a solvate.
 8. The active ingredientcombination of claim 7, wherein the analgesic compound is present in theform of a hydrate.
 9. The active ingredient combination of claim 1,wherein the COX-II inhibitor is selected from the group consisting ofcelecoxib, rofecoxib, etoricoxib, valdecoxib, parecoxib, etodolac,meloxicam and nimesulide.
 10. The active ingredient combination of claim1, wherein the COX-II inhibitor is celecoxib, rofecoxib or meloxicam.11. A pharmaceutical formulation comprising an active ingredientcombination according to claim 1 and a suitable auxiliary substance. 12.A method of alleviating pain in a mammal, said method comprisingadministering to said mammal an effective pain alleviating amount of anactive ingredient combination according to claim
 1. 13. The method ofclaim 12, wherein said pain is neuropathic pain, acute pain, chronicpain, visceral pain, cancer pain, or inflammatory pain.
 14. An activeingredient combination comprising: at least one analgesic compoundselected from the group consisting of:(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol and salts ofthe foregoing with a physiologically tolerated acid; and at least oneCOX-II inhibitor selected from the group consisting of selected from thegroup consisting of celecoxib, rofecoxib, etoricoxib, valdecoxib,parecoxib, etodolac and nimesulide.
 15. The active ingredientcombination of claim 14, wherein the analgesic compound is present inthe form of a hydrochloride or citrate salt.
 16. The active ingredientcombination of claim 14, wherein the analgesic compound is present inthe form of a free base.
 17. The active ingredient combination of claim14, wherein the analgesic compound is present in the form of an isolatedenantiomer or isolated diastereoisomer.
 18. The active ingredientcombination of claim 14, wherein the analgesic compound is present inthe form of a mixture of stereoisomers.
 19. The active ingredientcombination of claim 14, wherein the analgesic compound is present inthe form of a racemic mixture.
 20. The active ingredient combination ofclaim 14, wherein the analgesic compound is present in the form of asolvate.
 21. The active ingredient combination of claim 20, wherein theanalgesic compound is present in the form of a hydrate.
 22. Apharmaceutical formulation comprising an active ingredient combinationaccording to claim 14 and a suitable auxiliary substance.
 23. A methodof alleviating pain in a mammal, said method comprising administering tosaid mammal an effective pain alleviating amount of an active ingredientcombination according to claim
 14. 24. The method of claim 23, whereinsaid pain is neuropathic pain, acute pain, chronic pain, visceral pain,cancer pain or inflammatory pain.
 25. An active ingredient combinationcomprising: at least one analgesic compound selected from the groupconsisting of:(1R,2R)-3-(3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol; and salts ofthe foregoing with a physiologically tolerated acid; and at least oneCOX-II inhibitor selected from the group consisting of: celecoxib,rofecoxib, etoricoxib, valdecoxib, and parecoxib.
 26. The activeingredient combination of claim 25, which exhibits a supra-additive paineffect.